Abstract
The N141I mutation in presenilin (PS) 2 is tightly linked with a form of autosomal dominant familial Alzheimer's disease in the Volga German families. We previously reported that mouse brains harboring mutant PS2 contained increased levels of amyloid beta protein (Abeta) 42 in the Tris-saline-soluble fraction (Oyama, F., Sawamura, N., Kobayashi, K., Morishima-Kawashima, M., Kuramochi, T., Ito, M., Tomita, T., Maruyama, K., Saido, T. C., Iwatsubo, T., Capell, A., Walter, J., Grünberg, J., Ueyama, Y., Haass, C. and Ihara, Y. (1998) J. Neurochem. 71, 313-322). Here, using a new extraction protocol, we quantitated the Abeta40 and Abeta42 levels in the Tris-saline-insoluble fraction. The insoluble Abeta levels were found to be higher than the soluble Abeta levels, and the insoluble Abeta42 levels were markedly increased in mutant PS2 transgenic mice. To investigate the origin of the insoluble Abeta42, we prepared the detergent-insoluble, low density membrane fraction. This fraction from two independent lines of mutant PS2 transgenic mice contained remarkably increased levels of Abeta42 and significantly low levels of glycerophospholipids and sphingomyelin. This unexpected finding suggests that a large increase in the levels of Abeta42 in mutant PS2 mice is presumably induced through alterations of the lipid composition in the low density membrane domain in the brain.
Highlights
The N141I mutation in presenilin (PS) 2 is tightly linked with a form of autosomal dominant familial Alzheimer’s disease in the Volga German families
We examined whether the PS2 fragments and amyloid precursor protein (APP) and its fragments were present in the Low Density Membrane (LDM) fraction and, if these were present, whether these protein levels differed among W2, M1, and nontransgenic mice
One of the important findings in this study is that mutant PS2 linked to the Volga German families, N141I, had significant effects on the levels of amyloid  protein (A)42 in the TS-insoluble fraction of mouse brain
Summary
The N141I mutation in presenilin (PS) 2 is tightly linked with a form of autosomal dominant familial Alzheimer’s disease in the Volga German families. This fraction from two independent lines of mutant PS2 transgenic mice contained remarkably increased levels of A42 and significantly low levels of glycerophospholipids and sphingomyelin.
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